Treatment of chronic hepatitis C in hemodialysis patients


  • Marina Berenguer

    Corresponding author
    1. Hepatogastroenterology Service, Hospital La Fe, Facultad de Medicina de la Universidad de Valencia, Valencia, Spain and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    • Hepatogastroenterology Service, Hospital La Fe, Servicio de Medicina Digestivo, Avenida Campanar 21, Valencia 46009, Spain
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    • fax: 34-96-1973118

  • Potential conflict of interest: Nothing to report.


Hepatitis C virus (HCV) infection is especially problematic in patients with end-stage renal disease (ESRD) who are undergoing hemodialysis. Rates of HCV infection are higher among hemodialysis patients than in the general population, and several routes of transmission are thought to stem from the dialysis unit. Management of chronic hepatitis C is also more complicated in hemodialysis patients because of altered pharmacokinetics and a predisposition for drug-related toxicity, particularly ribavirin-induced anemia. Clinical trials of patients with chronic hepatitis C and healthy, functioning kidney grafts are rare because of the inherent dangers of graft rejection. As a result, most studies in patients with ESRD have focused on patients waiting for a kidney transplant. Additionally, because ribavirin is contraindicated in this patient population, many studies have examined monotherapy treatments. According to meta-analyses, conventional interferon alfa treatment yields a sustained virological response (SVR) rate of 37%, whereas studies of pegylated interferon alfa monotherapy have yielded SVR rates between 13% and 75%. Several small studies have also used the monitoring of ribavirin plasma concentrations or hemoglobin levels to facilitate the use of combination therapy. In light of the results from these clinical trials, we herein review treatment guidelines and recommend strategies to help optimize the treatment of patients with ESRD. Conclusion: There remains a lack of clarity surrounding the most effective treatment options for patients with chronic hepatitis C and ESRD. Treatment can be effective with many patients attaining SVR; however, unfavorable tolerability with interferon alfa–based therapy remains a concern and thus close supportive care should be aggressively pursued to help maintain adherence. (HEPATOLOGY 2008;48:1690–1699.)

Hepatitis C virus (HCV) infection levies a significant burden on patients with end-stage renal disease (ESRD). The prevalence of HCV infection in patients undergoing hemodialysis is greater than the incidence in the general population.1 Estimates in some geographical regions, such as Egypt, indicate that up to 80% of hemodialysis patients are infected with HCV. Further, across Western nations such as Italy, the prevalence of hepatitis C within the hemodialysis population can exceed 20%. In comparison, the prevalence of hepatitis C in the general population is less than 5% in most countries. Several routes of infection within dialysis units have been proposed as the source of transmission among patients.1, 2 Dialysis reuse, internal contamination of dialysis machines, shared medications such as heparin, and cross-contamination through staff or shared equipment have all been implicated. In many cases, simple lack of observance of standard hemodialysis unit precautions most likely leads to HCV transmission.1 Strict adherence to infection control procedures, including staff education, hand hygiene, appropriate management of the dialysis machine (use of transducer protectors, external cleaning, and disinfection of internal fluid pathways), and appropriate waste management, are among the most important procedures for minimizing HCV transmission in hemodialysis units.3

In patients with normal renal function, antiviral therapy is aimed at permanently eradicating HCV infection, and in doing so, improving liver histology, which in the long-term will likely result in a survival benefit. In patients with ESRD, the issue of antiviral therapy is even more relevant because HCV infection has been shown to impair survival in the hemodialysis patient as well as in patients after kidney transplantation. In addition, various patterns of glomerulonephritis have been observed in patients with chronic hepatitis C.4 Membranoproliferative glomerulonephritis (MPGN) with type II cryoglobulinemia is the predominant type of glomerulonephritis in patients infected with HCV, but other types also have been reported, including MPGN without cryoglobulinemia and membranous glomerulonephritis (see review by Kamar and colleagues for a full description of the pathology of HCV-related kidney disease4). Immune complexes comprising viral particles, anti-HCV antibodies, and other auto-antibodies such as rheumatoid factor become deposited in the glomeruli and are thought to contribute to HCV-related glomerulonephritis; however, the exact mechanisms underlying this process remain elusive, and why only a proportion of patients develop kidney lesions is unclear.4

Pegylated interferon (PEG-IFN) alfa-2a or alfa-2b plus ribavirin combination therapy is the standard of care for patients with chronic hepatitis C and normal renal function. In these patients, clinical experience during the past 5 years has advanced dramatically. Many important viral and host factors that affect response to therapy have been identified, which allows physicians to individualize therapy and maximize the likelihood of achieving a positive outcome. Unfortunately, the treatment of patients with hepatitis C and ESRD has not kept pace with findings elsewhere in this field, resulting in a significant gap in our understanding of the clinical management of hepatitis C. In the patient with hepatitis C and ESRD, altered drug pharmacokinetics, increased susceptibility to drug-related toxicity, the requirement for renal transplantation, and a modified course of disease are additional complicating factors. Therefore, treatment approaches for patients with hepatitis C and normal renal function cannot be routinely applied to those with renal dysfunction.

This review summarizes IFN-based antiviral therapy experiences, both in terms of sustained virological response (SVR) and of treatment-limiting tolerability, in patients with chronic hepatitis C and renal dysfunction. Most of the clinical evidence in this field is from small observational case series; few examples of well-designed, prospective clinical investigations exist. An integrated overview of existing data is presented, as are recommendations for future treatment strategies and areas in need of further investigation.


AASLD, American Association for the Study of Liver Diseases; AGA, American Gastroenterological Association; AUC, area under the plasma concentration time curve; CrCl, creatinine clearance; ESRD, end-stage renal disease; G, genotype; HCV, hepatitis C virus; HD, hemodynamics; IFN, interferon; MPGN, membranoproliferative glomerulonephritis; MU, million units; PEG-IFN, pegylated interferon; RT, renal transplant; SVR, sustained virological response.

Pharmacokinetics of IFN and Ribavirin in ESRD

The kidney plays a major role in the elimination of IFN and ribavirin. As a result, the pharmacokinetics of conventional IFN alfa, PEG-IFN alfa, and ribavirin are each substantially altered in patients with chronic hepatitis C and ESRD compared with those with normal renal function.

The kidney is the main site for IFN degradation; therefore, renal dysfunction is predicted to affect IFN pharmacokinetics.5 Indeed, in hemodialysis patients, the half-life of conventional IFN alfa-2b is significantly longer (10 versus 6 hours; P < 0.05) and the area under the plasma concentration time curve (AUC) is significantly greater (756 versus 324 IU/hour · mL; P < 0.05) than in patients who are nonuremic, even when the dose given to hemodialysis patients is 50% of that in the nonuremic controls.6 Similar observations regarding the impact of renal dysfunction on PEG-IFN alfa-2b have been reported.7 In patients with creatinine clearance (CrCl) <30 mL/minute, maximum plasma concentration and AUC are increased by 90%, and half-life is increased by 40% compared with control patients with normal renal function. The detrimental impact of renal dysfunction on the pharmacokinetics of PEG-IFN alfa-2b is not exacerbated by hemodialysis, and there is no difference in venous or arterial concentrations of PEG-IFN alfa in patients undergoing hemodialysis.7 In patients with moderate renal dysfunction (CrCl, 30-50 mL/minute), the PEG-IFN alfa-2b dose should be reduced by 25%. In patients with severe renal dysfunction (CrCl, 10-29 mL/minute), including those undergoing hemodialysis, the PEG-IFN alfa-2b dose should be reduced by 50%. Furthermore, if a decrease in renal function is observed during treatment, PEG-IFN alfa-2b should be discontinued.8 In contrast, because there is a 25%-45% reduction in clearance of PEG-IFN alfa-2a in patients with ESRD undergoing hemodialysis, a dose reduction from 180 μg/week to 135 μg/week is recommended.9

In patients with CrCl between 10 and 30 mL/minute, the AUC for ribavirin is three-fold greater than for patients with CrCl >90 mL/minute.10 Similarly, there is a two-fold increase in the AUC in patients with CrCl of 30 to 60 mL/minute.10 As a result of this pronounced increase in drug exposure and the accompanying elevated risk for drug-related toxicity, ribavirin is contraindicated in patients with CrCl <50 mL/minute.10 Ribavirin is not effectively removed by hemodialysis.

Treatment of Hepatitis C in Patients with Renal Dysfunction Requiring Hemodialysis and After Renal Transplantation

Unfortunately, patients with renal dysfunction are particularly vulnerable to the tolerability issues associated with therapy with PEG-IFN alfa plus ribavirin. As discussed, ribavirin is contraindicated in patients with CrCl values below 50 mL/minute, precluding its use in almost all patients receiving hemodialysis, including those listed for transplantation. Conversely, in patients with renal dysfunction who have received new grafts, the immunostimulant properties of IFN-based therapies are directly at odds with the immunosuppression required for effective engraftment. Therefore, in any patient who has recently received a functioning allograft, the risk of acute rejection often precludes the use of IFN-based therapy.

To date, the majority of published studies have investigated the use of conventional IFN alfa or PEG-IFN alfa monotherapy in patients with chronic hepatitis C who received hemodialysis before transplantation; however, most reports were retrospective descriptions of small case series. In general, there is a paucity of studies evaluating the use of PEG-IFN alfa, either alone or in combination with ribavirin. Similarly, a small number of case reports describe the treatment of patients with chronic hepatitis C after transplantation. However, these studies primarily involve patients with declining graft function; reports on the treatment of patients with chronic hepatitis C who have received functioning kidney grafts are extremely rare.

Hemodialysis Patients with Chronic Hepatitis C Awaiting Renal Transplantation

Conventional IFN Alfa Monotherapy.

Most studies investigating the use of conventional IFN alfa monotherapy in patients with chronic hepatitis C awaiting renal transplant are limited by small patient numbers, poor design features, or both (Table 1).6, 11–19 The clinical applicability of conventional IFN alfa monotherapy is captured in the results of two meta-analyses.20, 21 The first analysis20 included 14 studies with 269 patients, and the second analysis21 included 11 studies with 213 patients. Nine studies were common to both analyses. Studies included in the meta-analyses were typically small (fewer than 20 patients). Conventional IFN alfa was generally administered at a dose of 3 million units (MU) three times weekly for 6 or 12 months, with doses ranging from 1 to 6 MU. In general, encouraging SVR rates (37% within a predominantly genotype 1 [G1] cohort) were reported.20 In one of the meta-analyses,20 71 of 269 patients (26%) discontinued IFN monotherapy because of an adverse event (Fig. 1).20 Furthermore, biochemical response (normalization of alanine aminotransferase [ALT]) at the end of treatment was attained by 50%-100% of treated patients across all studies in this meta-analysis; however, the extent to which normalization of ALT was sustained following cessation of treatment is less clear. After 6 months of follow-up, some studies in this meta-analysis reported a rapid decline in biochemical response rates during follow-up, whereas other studies showed biochemical response was well maintained in the majority of patients after follow-up.20 In addition, Degos and colleagues12 performed liver biopsies before and after treatment and found that Knodell fibrosis scores remained stable in 14 of 20 (70%) and improved in two of 20 (10%) patients treated with IFN-alfa (3 MU three times weekly) for 48 weeks; the four remaining patients showed a one-point increase in fibrosis score. Knodell activity scores were stable in 12 patients (60%) and improved in two patients (10%).12

Table 1. Clinical Trials of IFN Monotherapy in Hemodialysis Patients with Chronic Hepatitis C
StudyPatient Population (n)Treatment RegimenCompleted TreatmentEOTSVRSerious Adverse Events Requiring Discontinuation
  • *

    Study interrupted because of frequency and severity of side effects.12

  • Two patients experienced relapses 6 and 9 months after transplantation.

  • NR, not reported; RT, renal transplant.

Rocha et al.11Tx-naive HCV (+) HD (46) ·1 G1: 86% ·2 RT: 20% ·3 Bridging fibrosis: 39%IFN-alfa (3 MU 3× week) for 12 months29/46 (63%)19/46 (41%)10/46 (22%)Anemia, n = 4 Diarrhea, n = 2 Hemorrhagic stroke, n = 1 Amnesia, n = 1 Bone pain, n = 1 Pneumonia, n = 1 Hepatic encephalopathy, n = 1
Degos et al.12*Tx-naive HCV (+) HD (37) G1: 78%IFN-alfa (3 MU 3× week) for 48 weeks18/37 (49%)12/37 (32.4%)7/37 (19%)Neuropsychiatric disturbance, n = 2 Asthenia, n = 9 Heart failure, n = 4 Digestive trouble, n = 3 Acute necrosis of kidney graft, n = 1
Chan et al.13HD HCV (+) pts (11) G1: 91%IFN-alfa 1.5 MU 3× week for 2 weeks, then 3 MU 3× week for 24 weeks11/11 (100%)11 (100%)3 (27%) 
Rivera et al.14HCV (+) HD (27)IFN-alfa (3 MU, 2 to 3× week) for 6 to 12 months (n = 20) or PEG-IFN alfa-2a (135 μg/week) for 12 months (n = 7)NR13/27 (48.1%) [IFN alfa, 10/20; PEG-IFN alfa, 3/7]11/27 (40.7%)Pancytopenia/intolerance of previous kidney graft, n = 3
Grgurevic et al.19HCV (+) HD (15)IFN-alfa (3 MU 3× week) for 6 months or (5 MU 3× week) for 3 months, then 5 MU/week for 3 months13/15 (86.7%)9/15 (60%)6/15 (40%)Transient ischemic attack, n = 1 Profound leukopenia, n = 1
Uchihara et al.6HCV (+) Maintenance HD (9)IFN alfa (3-6 MU/d) for 2 weeks, then 3 MU 3× week for 24 weeks6/9 (66.6%)NR3/9 (33.3%)Depression Loss of consciousness Persistent high-grade fever
Espinosa et al.16HCV (+) HD (13) G1: 40%IFN alfa (3 MU) for 1 year10/13 (76.9%)8/13 (61.5%)6/13 (46.2%)Severe flulike syndrome Severe leukopenia/thrombocytopenia Seizure
Mahmoud et al.17HCV (+) HD (18)IFN-alfa (3 MU 3 × week) for 6 months16/18 (88.9%)NR8/18 (44.4%)Leukopenia, n = 2
Ozdemir et al.18HCV (+) HD (20)IFN-alfa (6 MU 3 × week) for 6 months (n = 10) IFN-alfa (3 MU 3× week) for 12 months (n = 10)NR15/20 (75%)8/20 (40%)NR
Figure 1.

Causes of IFN alfa monotherapy discontinuation in 14 clinical trials of patients with ESRD receiving hemodialysis.20

The results of these meta-analyses are supported by data from a recent clinical trial that included 46 patients with chronic hepatitis C and ESRD who received conventional IFN alfa (3 MU three times weekly) monotherapy for 12 months.11 Overall, 10 of 46 patients (22%) attained SVR; 11 patients (24%) experienced serious adverse events and discontinued treatment.11

SVR rates are up to two-fold lower in treatment-naive patients with chronic hepatitis C and normal renal function receiving conventional IFN monotherapy (13%-19%)22, 23 than in patients with chronic hepatitis C and impaired renal function (33%-37%),20, 21 indicating that this treatment is more effective in hemodialysis patients. Increased bioavailability resulting from reduced renal elimination in hemodialysis patients may account for the observed efficacy differences; however, this hypothesis is unproven.

PEG-IFN alfa Monotherapy.

Several studies have investigated PEG-IFN alfa monotherapy for hepatitis C in patients with renal dysfunction.24–32 However, most studies were small and included 10 patients or fewer; only four studies included more than 10 patients.24, 25, 31, 32 Common results included low SVR rates and an unfavorable tolerability profile. SVR rates ranged from 30%-75%, with better response rates generally reported in studies with 10 or fewer patients.26–29 Two of the larger analyses produced SVR rates of 12%-14%,24, 25 whereas two moderately sized studies produced SVR rates of 50% (n = 34) and 75% (n = 12) (Fig. 2).24, 25, 31, 32

Figure 2.

Treatment of patients with chronic hepatitis C who were undergoing hemodialysis with PEG-IFN alfa monotherapy.24, 25, 31, 32 EOT, end-of-treatment response (undetectable HCV RNA at week 48 of treatment); EVR, early virological response (undetectable HCV RNA at week 12); SVR, sustained virological response (undetectable HCV RNA 6 months after completion of therapy); PEG-IFN, pegylated interferon.

Covic et al.24 reported results from a study of 78 hemodialysis patients with chronic hepatitis C who received PEG-IFN alfa-2a (135 μg/week) at the end of each dialysis session for 48 weeks. Only 21 patients (27%) completed 48 weeks of therapy, and 83% of patients reported at least one adverse event, the most common of which were influenza-like symptoms (64%) and asthenia (31%). Of note, 25 patients (32%) did not complete their planned treatment schedule because of multiple minor adverse events. In addition, seven patients discontinued treatment because of serious adverse events, and four patients died.24 Fifteen patients (19%) had undetectable HCV RNA levels at the end of therapy. Of these, 11 patients (14%) attained SVR, but four (27%) experienced relapse.24

In another prospective, noncomparative study, Tan et al.31 reported an SVR rate of 50% among 34 hemodialysis patients with chronic hepatitis C receiving PEG-IFN alfa-2b monotherapy.31 In this study, a starting dose of 0.5 μg/kg/week was initiated, with dose increments of 0.25 μg/kg/week every 4 weeks up to a maximum of 1.0 μg/kg/week after 48 weeks of treatment in patients infected with G1 HCV and after 24 weeks in G2/3 patients. Although 97% of patients reached this target dose, 21% were unable to maintain that level. Overall, 32% of patients did not complete therapy because of adverse tolerability. Anemia was the most frequent adverse event, and 65% of patients required blood transfusions.

Kokoglu et al.32 treated 12 hemodialysis patients with PEG-IFN alfa-2a (135 μg/week) for 48 weeks. Nine patients (75%) had undetectable HCV RNA at week 12, and 10 patients (83.4%) attained end-of-treatment response. During the 6-month follow-up period, nine patients continued to demonstrate undetectable HCV RNA (SVR, 75%), and one patient experienced relapse. There were no discontinuations because of adverse events, although nine patients experienced declines in hemoglobin levels that were managed with erythropoietin. Thrombocytopenia and leukopenia were also observed in four patients (33%) each.32

Finally, Russo et al.25 investigated the efficacy and safety of two dosages of PEG-IFN alfa-2b, 1.0 μg/kg/week and 0.5 μg/kg/week, administered for up to 48 weeks. In this study, SVR was attained by two of nine patients receiving the 1.0-μg/kg dose and by none of seven patients receiving the 0.5-μg/kg dose. As observed in other studies, tolerability was a significant concern; 44% of patients did not complete the allotted regimen. Despite the low patient numbers in this study, the authors suggested that PEG-IFN alfa-2b at a dose of 0.5 μg/kg/week may be insufficient to achieve meaningful rates of SVR.25

In general, adverse tolerability is a particular concern with PEG-IFN alfa monotherapy among patients receiving hemodialysis, and these studies suggest 30%-50% of patients do not complete therapy because of treatment-related adverse events. Optimizing supportive care in these patients may be a critical step forward to help promote adherence.

Combination Therapy.

Several small case reports or case series have examined the use of ribavirin in combination with IFN-based therapy in patients with chronic hepatitis C and poor renal function.33–41 Despite starting doses of ribavirin far below those currently recommended for the treatment of chronic hepatitis C (200 mg/week to 400 mg/day versus 1000-1200 mg/day), declining hemoglobin levels are a common feature of these studies even with the widespread use of erythropoietin. Overall, SVR rates, where reported, were generally low. Among the best treatment outcomes are those reported by Bruchfeld et al.34 (SVR attained in three of six patients receiving PEG-IFN alfa plus ribavirin [200-400 mg/day]), van Leusen et al.40 (SVR attained in five of seven patients receiving PEG-IFN alfa-2a plus ribavirin [200 mg every 2 days]), and Mousa et al.35 (SVR attained in 11 of 20 patients receiving conventional IFN alfa [3 MU three times weekly] and ribavirin [200 mg three times weekly]). More recently, Carriero and colleagues41 reported SVR rates of 28.6% among patients infected with chronic hepatitis C who were listed for renal transplant and who received PEG-IFN alfa-2a (135 μg/week) plus ribavirin (200 mg/day). Although ribavirin doses were very low in these studies, Tan et al.37 reported that ribavirin plasma concentrations of 2517 ng/mL were achieved in hemodialysis patients receiving ribavirin 200 mg/day. This level is comparable to the plasma ribavirin levels of approximately 2300 ng/mL reported for patients with chronic hepatitis C and normal renal function receiving ribavirin 1200 mg/day.37, 42 These findings have led to the use of an individualized approach to ribavirin administration in which dose levels are adjusted to maintain plasma concentrations within a target therapeutic window. Bruchfeld et al.33 (the originators of this novel individualized ribavirin administration) found that plasma ribavirin concentrations of 9-15 μmol/L could be achieved with doses of 200 mg four times weekly, 200 mg/day, or 400 mg three times weekly. In this study, the target ribavirin plasma concentration was 10-15 μmol/L, a range chosen to coincide with the steady state ribavirin concentrations of 7-17 μmol/L that were recorded in a reference population of patients with chronic hepatitis C and normal renal function. The study by van Leusen et al.40 also used ribavirin plasma monitoring and achieved an SVR rate of 71% in treated patients. In this study, all treated patients completed their planned therapy, and four patients required blood transfusion for anemia.

More recently, Rendina et al.43 documented the largest case series evaluation of combination therapy with PEG-IFN alfa-2a (135 μg/week) plus ribavirin (200 mg/day) for 24 (non-G1) or 48 (G1) weeks in patients with chronic hepatitis C who were receiving hemodialysis. During the study, ribavirin doses were adjusted according to ribavirin plasma concentrations (target, 10-15 μmol/L) and hemoglobin levels (minimum, 8.5 g/dL). Erythropoietin and granulocyte colony-stimulating factor were used, as appropriate, to support hemoglobin and neutrophil levels. This study included 35 treated patients (16 G1 and 19 non-G1). One patient with G1 HCV was withdrawn from treatment early because of nonresponse, and four non-G1 patients were withdrawn early for renal transplantation (n = 2) or because of anemia (n = 1) or dermatitis (n = 1). Thus, 15 of the 16 patients with G1 completed 48 weeks of therapy, and all were virus free (<50 IU/mL serum HCV RNA) at the end of follow-up. In addition, all 19 patients infected with non-G1 HCV (those who did and did not complete therapy) had undetectable HCV RNA at the time of their final dose and remained free of HCV RNA during 24 weeks of follow-up. In total, 34 of 35 (97%) treated patients, including those with treatment-limiting adverse events, attained SVR.43

End-stage renal failure is also frequently encountered in patients who have undergone orthotopic liver transplantation, attributed largely to the nephrotoxicity associated with calcineurin inhibitor use. Rates of renal dysfunction in liver transplant recipients may be even higher among those with recurrent HCV infection because of the concurrent MPGN.44, 45 A recent study showed an association between ribavirin-related toxicity and declining renal function in patients with hepatitis C after orthotopic liver transplantation.46 These observations suggest that lower doses of ribavirin also may be considered in these patients, with the aim of reducing drug-related toxicity and specifically lessening the requirement for erythropoietin (see review by Berenguer et al.47 for a full description of the treatment of recurrent hepatitis C in liver transplant recipients).

Collectively, these studies advocate using an individualized ribavirin dosage (based on ribavirin plasma levels and hemoglobin concentration) of approximately 200 mg/day to provide optimal antiviral activity. Larger prospective studies in this setting are clearly warranted to determine the most effective dosing regimen for ribavirin.

Patients with Chronic Hepatitis C After Renal Transplantation.

Hepatitis C progresses rapidly after renal transplantation. Immunosuppression, particularly with corticosteroids, is associated with a 10-fold to 100-fold increase in viral load and rapid progression to cirrhosis. In addition, HCV infection and IFN alfa–based antiviral therapy may each adversely affect graft survival and function independently. Weclawiack et al.48 recently updated their longitudinal observation study of 261 kidney transplantations, of which 87 were performed in patients with hepatitis C (Fig. 3). In this study, the proportion of patients with functioning allografts was significantly higher among control patients not infected with hepatitis C than among those with hepatitis C (53% versus 25%, P < 0.0001). Correspondingly, the proportion of patients whose graft failed 12 months or more after transplantation was significantly greater among patients with hepatitis C than among controls (55% versus 28%, P < 0.0001). In addition, among patients with hepatitis C whose allograft failed, 11 were offered IFN alfa–based therapy. Of these, acute rejection necessitating transplantectomy developed in four patients (36%). Histological examination showed acute cellular and vascular lesions as well as chronic allograft lesions. Conversely, only 16% of patients with hepatitis C who did not receive IFN alfa required transplantectomy.

Figure 3.

Effect of hepatitis C on kidney graft function. The adverse impact of chronic hepatitis C on graft function and survival among patients with and without chronic hepatitis C.48

Clinical precedent for treating patients infected with hepatitis C who have functioning allografts is lacking, and data supporting the most effective regimen or appropriate concurrent immunosuppression are sparse. Although examples of successful treatment outcomes in this population exist,49 reports of suspected IFN alfa–induced acute rejection confound interpretation.50 Overall, IFN alfa–based antiviral therapy for patients with hepatitis C with functioning renal allografts should be reserved for those with limited alternative options and for those for whom antiviral therapy is deemed imperative, such as patients with severe cholestatic hepatitis.51

In patients with failed allografts, one small study suggests that IFN alfa–based antiviral therapy may be of benefit. Casanovas-Taltavull52 reported a case series including 16 patients with hepatitis C and failed kidney allografts. Of the 16 patients, eight attained sustained HCV clearance, and three who had graft intolerance/noninfectious fever required graft embolization. Thus, in patients with nonfunctioning renal allografts, IFN alfa–based therapy may be an option. In this population, the potential benefits of viral eradication should be weighed against the risk for acute rejection, necessitating transplantectomy or embolization.

Because of concerns regarding acute graft rejection in patients receiving IFN therapy, a small number of studies have considered the use of ribavirin monotherapy to treat chronic hepatitis C in renal transplant recipients.53–55 In general, ribavirin monotherapy has little or no effect on HCV RNA levels, but reports of normalization of ALT levels have been documented in some patients. Furthermore, Fontaine et al.53 reported significant improvement in hepatic necroinflammatory activity and fibrosis in renal transplant recipients with hepatic bridging fibrosis or cirrhosis who were receiving ribavirin monotherapy (mean dose 724 mg/day for 22.6 months),55 although these data have not been replicated in other studies.

Treatment Recommendations

Guidelines from the American Gastroenterological Association (AGA) and the American Association for the Study of Liver Diseases (AASLD) indicate that, because of a lack of robust prospective clinical data, the role of antiviral therapy in patients with ESRD remains undefined.56, 57 AGA and AASLD guidelines recommend reduced doses of PEG-IFN alfa as monotherapy and consider ribavirin a contraindication in this setting.56, 57 A treatment algorithm for the treatment of patients with chronic kidney disease and hepatitis C infection is depicted in Figure 4.59, 60

Figure 4.

Treatment algorithm for the management of patients with chronic kidney disease and hepatitis C infection (modified from the recently published KDIGO clinical practice guidelines). Chronic kidney disease stage 1, GFR ≥90 mL/minute/1.73 m2; stage 2, 60-89 mL/minute/1.73 m2; stage 3, 30-59 mL/minute/1.73 m2; stage 4, 15-29 mL/minute/1.73 m2; stage 5, <15 mL/minute/1.73 m2 (or dialysis). GFR, glomerular filtration rate; HCV, hepatitis C virus; HD, hemodialysis; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response.

All hemodialysis patients with confirmed detectable HCV RNA who have not previously received treatment for HCV infection should be considered as candidates for IFN alfa–based antiviral therapy. Patients without advanced fibrosis (METAVIR score F0-F2) may also be listed for transplantation; however, efforts aimed at viral eradication before transplantation should be actively pursued. Patients with bridging fibrosis and compensated cirrhosis should also receive antiviral therapy and may be considered transplant candidates if SVR is attained; patients with decompensated cirrhosis are generally not candidates for isolated kidney transplantation but may be considered for combined liver-kidney transplantation. The potential for IFN-induced acute rejection, coupled with reduced graft survival among patients with hepatitis C compared with patients who are not infected, precludes antiviral therapy in the post-transplantation setting.

Decisions regarding the most appropriate treatment regimen are difficult because of the lack of comparative data in this field. The first decision to face physicians is that of combined versus monotherapy treatment. Ribavirin is contraindicated in patients with CrCl <50 mL/minute10; therefore, monotherapy is warranted in these patients. Data regarding the use of ribavirin in hemodialysis patients remains scarce, though recent outcomes using ribavirin dosed according to serum ribavirin concentrations and hemoglobin levels are encouraging.40, 43 Until further data are reported, however, routine use of ribavirin in hemodialysis patients cannot be recommended, and at this time combination therapy with IFN alfa and ribavirin should be considered only within the context of a clinical trial.

If monotherapy is pursued, the decision remains whether to administer conventional IFN alfa or PEG-IFN alfa. In a recent meta-analysis of individual patient data from 20 clinical studies, Gordon et al.58 reported SVR rates of 41% in patients receiving conventional IFN alfa and 37% in patients receiving PEG-IFN alfa. Unfortunately, this analysis excluded certain studies that did not report individual patient data. As a result, several PEG-IFN alfa studies that recruited large patient numbers were excluded. It is unknown whether inclusion of these data would have substantially altered the findings of this study. In this setting, the benefits of PEG-IFN alfa reside in the convenience of once-weekly dosing; PEG-IFN alfa monotherapy may be considered for patients who benefit from this attribute. However, no clear evidence exists for improved efficacy with either PEG-IFN alfa or conventional IFN for the remaining patients on hemodialysis; thus, further study is required to define the most appropriate therapy for these patients.

Additional evidence-based recommendations regarding the treatment of hepatitis C in hemodialysis patients, beyond the use of IFN-based monotherapy treatment in the pretransplantation setting, are not feasible at this time. The meta-analysis by Gordon et al.58 supports the use of a minimum 24-week treatment period, but a 48-week schedule should be considered for patients with HCV G1 infection. Ultimately, additional studies are required to improve our understanding of the optimized use of PEG-IFN alfa and to guide treatment recommendations.


Insufficient clinical data exist to support evidence-based recommendations for treating patients with chronic hepatitis C and ESRD. Although conventional IFN alfa has been largely replaced by PEG-IFN alfa in patients with normal renal function, evidence suggests that SVR rates are at least similar for conventional and PEG-IFN alfa in hemodialysis patients. Comparative studies are required to determine whether tolerability and cost issues can also help differentiate these treatment options. Although ribavirin is contraindicated in patients with CrCl <50 mL/minute, recent evidence using individualized dosing indicates that ribavirin treatment may contribute to more favorable clinical outcomes.

Despite the lack of clarity surrounding the most effective treatment options for patients with chronic hepatitis C and ESRD, several consistent themes persist. Hemodialysis patients are particularly susceptible to unfavorable tolerability with IFN alfa–based therapy. Supportive care such as growth factor supplementation should be aggressively pursued to help maintain adherence. In addition, several studies with IFN alfa–based therapy have demonstrated SVR rates of 50% or greater, indicating that many hemodialysis patients with hepatitis C can benefit from treatment.


Writing assistance was provided by Tim Ibbotson, Ph.D., and Maribeth Bogush, Ph.D. This assistance was funded by Schering-Plough.